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1.
J Surg Res ; 291: 51-57, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37348436

RESUMO

INTRODUCTION: Alarming rates of burnout in surgical training pose a concern due to its deleterious effects on both patients and providers. Datum remains lacking on rates of burnout in surgical residents based on race and ethnicity. This study aims to document the frequency of burnout in surgical residents of racially underrepresented backgrounds and elucidate contributing factors. METHODS: A 35-question anonymized survey was distributed to general surgery residents from 23 programs between August 2018 and May 2019. This survey was designed from the validated Maslach Burnout Inventory, and included additional questions assessing participant demographics, educational, and social backgrounds. Responses were analyzed utilizing chi-square tests and Wilcoxon rank sum tests. There was also a free response portion of the survey which was evaluated using thematic analysis. RESULTS: We received 243 responses from 23 general surgery programs yielding a 9% (23/246) program response rate and 26% (243/935) response rate by surgical residents. One hundred and eighty-five participants (76%) identified as nonunderrepresented in medicine and 58 (24%) of participants identified as underrepresented in medicine. Fifty-three percent were male and 47% female. Overall, sixty-six percent of all surgical residents (n = 161) endorsed burnout with racially underrepresented residents reporting higher rates of burnout at 76% compared to 63% in their nonunderrepresented counterparts (P = 0.07). CONCLUSIONS: Although the generalizability of these results is limited, higher rates of reported burnout in racially underrepresented trainees noted in our study illuminates the need for continual dialogue on potential influencing factors and mitigation strategies.


Assuntos
Esgotamento Profissional , Internato e Residência , Humanos , Masculino , Feminino , Esgotamento Profissional/epidemiologia , Esgotamento Profissional/etiologia , Inquéritos e Questionários , Escolaridade
2.
Ann Surg ; 276(3): e141-e176, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35848728

RESUMO

OBJECTIVE: To develop evidence-based recommendations for safe, effective, and appropriate treatment of secondary (SHPT) and tertiary (THPT) renal hyperparathyroidism. BACKGROUND: Hyperparathyroidism is common among patients with chronic kidney disease, end-stage kidney disease, and kidney transplant. The surgical management of SHPT and THPT is nuanced and requires a multidisciplinary approach. There are currently no clinical practice guidelines that address the surgical treatment of SHPT and THPT. METHODS: Medical literature was reviewed from January 1, 1985 to present January 1, 2021 by a panel of 10 experts in SHPT and THPT. Recommendations using the best available evidence was constructed. The American College of Physicians grading system was used to determine levels of evidence. Recommendations were discussed to consensus. The American Association of Endocrine Surgeons membership reviewed and commented on preliminary drafts of the content. RESULTS: These clinical guidelines present the epidemiology and pathophysiology of SHPT and THPT and provide recommendations for work-up and management of SHPT and THPT for all involved clinicians. It outlines the preoperative, intraoperative, and postoperative management of SHPT and THPT, as well as related definitions, operative techniques, morbidity, and outcomes. Specific topics include Pathogenesis and Epidemiology, Initial Evaluation, Imaging, Preoperative and Perioperative Care, Surgical Planning and Parathyroidectomy, Adjuncts and Approaches, Outcomes, and Reoperation. CONCLUSIONS: Evidence-based guidelines were created to assist clinicians in the optimal management of secondary and tertiary renal hyperparathyroidism.


Assuntos
Hiperparatireoidismo Secundário , Falência Renal Crônica , Cirurgiões , Humanos , Hiperparatireoidismo Secundário/etiologia , Hiperparatireoidismo Secundário/cirurgia , Rim , Falência Renal Crônica/complicações , Falência Renal Crônica/cirurgia , Paratireoidectomia/métodos , Estados Unidos/epidemiologia
3.
BMC Public Health ; 21(1): 958, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34016065

RESUMO

BACKGROUND: In the last decade surgical care has been propelled into the public health domain with the establishment of a World Health Organisation (WHO) designated programme and key publications. The passing of the historic World Health Assembly Resolution (WHA) acknowledged surgical care as a vital component towards achieving Universal Health Coverage (UHC). We conducted the first worldwide survey to explore the perception of surgical care as a public health issue. METHOD: The anonymous, cross sectional survey targeted worldwide participants across a range of professional backgrounds, including non-medical using virtual snowball sampling method (in English) using Google Forms (Google Inc., Mountain View, CA, USA) from 20th February 2019 to 25th June 2019. The survey questions were designed to gauge awareness on Sustainable Development Goals (SDGs), UHC, WHO programmes and key publications on surgical care as well as perception of surgical care as a priority topic in public health. RESULTS: The survey was completed by 1954 respondents from 118 countries. Respondents were least aware of surgical care as a teaching topic in public health courses (27%; n = 526) and as a WHO programme (20%; n = 384). 82% of respondents were aware of UHC (n = 1599) and of this 72% (n = 1152) agreed that surgical care fits within UHC. While 77% (n = 1495) of respondents were aware of SDGs, only 19% (n = 370) agreed that surgery was a priority to meet SDGs. 48% (n = 941) rated surgical care as a cost-effective component of Primary Health Care. 88% (n = 1712) respondents had not read the WHA Resolution on 'Strengthening emergency and essential surgical care and anaesthesia as a component of UHC'. CONCLUSION: There is still a widespread gap in awareness on the importance of surgical care as a public health issue amongst our respondents. Surgical care was not seen as a priority to reach the SDGs, less visible as a WHO programme and not perceived as an important topic for public health courses.


Assuntos
Saúde Pública , Cobertura Universal do Seguro de Saúde , Estudos Transversais , Saúde Global , Humanos , Percepção
4.
Eur J Trauma Emerg Surg ; 47(5): 1591-1598, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32157342

RESUMO

OBJECTIVES: The mortality rate from road traffic accidents (RTAs) in Nigeria is almost double that of the USA. In Nigeria, the first emergency medical services (EMS) system was established in March 2001, The Lagos State Ambulance Service (LASAMBUS). The objectives of this study are to (1) determine the burden of RTAs in Lagos, (2) assess RTA call outcomes, and (3) analyze LASAMBUS's response time and causes for delay. METHODOLOGY: We reviewed completed LASAMBUS intervention forms spanning December 2017 to May 2018. We categorized the call outcomes into five groups: I. Addressed Crash, II. No Crash (False Call), III. Crash Already Addressed, IV. Did Not Respond, and V. Other. We further explored associations between the (1) causes for delay and outcomes and (2) response times and the outcomes. RESULTS: Overall, we analyzed 1352 intervention forms. We found that LASAMBUS did not address 53% of the RTA calls that they received. Of this, Outcome II. No Crash (False Call) accounted for 26% and Outcome III. Crash Already Addressed accounted for 22%. Self-reported causes for delay were recorded in 180 forms, representing 13.7% of the RTA burden. Traffic congestion accounted for 60% of this distribution. CONCLUSION: LASAMBUS response rates are significantly lower than response rates in high-income countries such as the USA and lead to increased RTA mortality rates. Eliminating causes for delay will improve both LASAMBUS effectiveness and RTA victims' health outcomes. Changing the public perception of LASAMBUS and standardizing LASAMBUS' contact information will aid this as well.


Assuntos
Ambulâncias , Serviços Médicos de Emergência , Acidentes de Trânsito , Humanos , Nigéria
5.
Proc Natl Acad Sci U S A ; 117(31): 18401-18411, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32690709

RESUMO

Disparities in cancer patient responses have prompted widespread searches to identify differences in sensitive vs. nonsensitive populations and form the basis of personalized medicine. This customized approach is dependent upon the development of pathway-specific therapeutics in conjunction with biomarkers that predict patient responses. Here, we show that Cdk5 drives growth in subgroups of patients with multiple types of neuroendocrine neoplasms. Phosphoproteomics and high throughput screening identified phosphorylation sites downstream of Cdk5. These phosphorylation events serve as biomarkers and effectively pinpoint Cdk5-driven tumors. Toward achieving targeted therapy, we demonstrate that mouse models of neuroendocrine cancer are responsive to selective Cdk5 inhibitors and biomimetic nanoparticles are effective vehicles for enhanced tumor targeting and reduction of drug toxicity. Finally, we show that biomarkers of Cdk5-dependent tumors effectively predict response to anti-Cdk5 therapy in patient-derived xenografts. Thus, a phosphoprotein-based diagnostic assay combined with Cdk5-targeted therapy is a rational treatment approach for neuroendocrine malignancies.


Assuntos
Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Tumores Neuroectodérmicos/tratamento farmacológico , Fosfoproteínas/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Quinase 5 Dependente de Ciclina/antagonistas & inibidores , Quinase 5 Dependente de Ciclina/genética , Quinase 5 Dependente de Ciclina/metabolismo , Xenoenxertos , Humanos , Camundongos , Neoplasias/genética , Tumores Neuroectodérmicos/genética , Tumores Neuroectodérmicos/metabolismo , Fosfoproteínas/análise , Fosfoproteínas/genética , Fosforilação
6.
World J Surg ; 43(3): 812-817, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30483883

RESUMO

BACKGROUND: Time to hormonal control after definitive management of hyperthyroidism is unknown but may influence patient and physician decision making when choosing between treatment options. The hypothesis is that the euthyroid state is achieved faster after thyroidectomy than RAI ablation. METHODS: A retrospective review of all patients undergoing definitive therapy for hyperthyroidism was performed. Outcomes after thyroidectomy were compared to RAI. RESULTS: Over 3 years, 217 patients underwent definitive therapy for hyperthyroidism at a county hospital: 121 patients received RAI, and 96 patients underwent thyroidectomy. Age was equivalent (p = 0.72). More males underwent RAI (25% vs 15%, p = 0.05). Endocrinologists referred for both treatments equally (p = 0.82). Both treatments were offered after a minimum 1-year trial of medical management (p = 0.15). RAI patients mostly had Graves (93%), versus 73% of thyroidectomy patients (p < 0.001). Thyroidectomy patients more frequently had eye symptoms (35% vs 13%, p < 0.001), compressive symptoms (74% vs 15%, p < 0.001), or were pregnant/nursing (14% vs 0, p < 0.001). While the thyroidectomy patients had a documented discussion of all treatment modalities, 79% of RAI patients did not have a documented discussion regarding the option of surgical management (p < 0.001). Both treatment groups achieved an euthyroid state (71% vs 65%, p = 0.39). Thyroidectomy patients became euthyroid faster [3 months (2-7 months) versus 9 months (4-14 months); p < 0.001]. CONCLUSIONS: Thyroidectomy for hyperthyroidism renders a patient to an euthyroid state faster than RAI. This finding may be important for patients and clinicians considering definitive options for hyperthyroidism.


Assuntos
Doença de Graves/terapia , Radioisótopos do Iodo/uso terapêutico , Tireoidectomia , Adulto , Comunicação , Feminino , Doença de Graves/sangue , Doença de Graves/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Educação de Pacientes como Assunto , Estudos Retrospectivos , Fatores de Tempo , Tri-Iodotironina/sangue
8.
Burns ; 44(7): 1839-1843, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30072197

RESUMO

BACKGROUND: The last generation has seen Ethiopia, a low income country with a population of 100 million people, undergo a marked increase in urbanization and development. The effects of these demographic changes on the epidemiology of burn risk and thermal injury in Ethiopia are unknown. This gap constitutes a major barrier to the creation of effective burn prevention programs. METHODS: Yekatit 12 Hospital in Addis Ababa is the only burn unit in Ethiopia. In this cross sectional retrospective study, we identified and reviewed all admissions due to burn injury at that facility between 1/1/2016 and 12/31/2016. We then compared them to a previously published burn cohort treated at the same facility between 7/1/2001 and 9/31/2002. Chi square was used to compare proportions between the two samples. Continuous covariates are reported as descriptive data due to missing variance data in the 2001-02 publication. RESULTS: There were a total of 121 subjects in the 2001-02 sample and 176 subjects in the 2016 sample. The 2016 sample was found to have a significantly larger proportion of males (57%) as compared to the 2001-02 sample (36%) (p=0.0003) and a significantly higher proportion of electrical injuries (27%) than the previous cohort (5%) (p<0.0001). No significant differences were seen in mortality rates between the 2016 and 2001-02 cohorts (8% vs 12%, respectively, p=0.29) or in the regions of origin (44% outside Addis Ababa vs 54%, p=0.09) For the 2016 sample, the highest surviving Baux score was 76 while the mean Baux score for survivors was 29.6±20.11. CONCLUSION: As Ethiopia has become more industrialized over the last 15 years, the demographic pattern of burn injury has changed accordingly as electrical injuries have increased five-fold with males now constituting a majority of burn cases.


Assuntos
Queimaduras/epidemiologia , Saúde Pública , Adolescente , Adulto , Idoso , Amputação Cirúrgica/estatística & dados numéricos , Unidades de Queimados , Queimaduras/prevenção & controle , Queimaduras/terapia , Queimaduras por Corrente Elétrica/epidemiologia , Queimaduras por Corrente Elétrica/prevenção & controle , Queimaduras por Corrente Elétrica/terapia , Criança , Pré-Escolar , Estudos de Coortes , Culinária , Estudos Transversais , Epilepsia/epidemiologia , Epilepsia/terapia , Etiópia/epidemiologia , Feminino , Hospitalização , Humanos , Incidência , Lactente , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Distribuição por Sexo , Transplante de Pele/estatística & dados numéricos , Fatores de Tempo , Adulto Jovem
9.
J Surg Res ; 205(2): 272-278, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27664872

RESUMO

BACKGROUND: Preincision operating room (OR) preparation varies greatly. Cases requiring exacting preoperative setup may be more sensitive to inconsistent team members and trainees. Leadership and oversight by the surgeon may facilitate a timely start. The study hypothesized that early attending presence in the OR expedites surgery start time, improving efficiency, and decreasing cost. METHODS: Prospective data collection of endocrine surgery cases at an urban teaching hospital was performed. Time points recorded in minutes. Cost/min of OR time was $54. Patients classified as in the OR ≤10 min before attending arrival or >10 min before attending arrival. RESULTS: A total of 227 cases (166 thyroid, 54 parathyroid, 10 adrenal) were performed over 14 mo. Of the patients, 128 were in the OR ≤10 min before attending arrival, and 99 patients were >10 min (3 ± 3 min versus 35 ± 14 min, P < 0.01). The ≤10 min procedures started sooner after patient arrival in OR (40 ± 11 versus 63 ± 19, P < 0.01) which equated to $1202 of savings before incision. Although attending time in the OR before incision was equivalent between groups for adrenal and parathyroid, time to incision was shorter in the ≤10 min groups, saving $2416 ± 477 and $1458 ± 244, respectively (P < 0.01). Attending time in OR before thyroidectomy was 13 min longer in ≤10 min than >10 min (P < 0.01), but incisions were made 20 min sooner (P < 0.01) equating to $1076 ± 120 in savings. CONCLUSIONS: Early attending presence in the OR shortens time to incision. For parathyroid and adrenal cases, this does not require additional surgeon time. In ORs without consistent teams, early attending presence in the OR improves efficiency and yields significant cost savings.


Assuntos
Eficiência Organizacional , Procedimentos Cirúrgicos Endócrinos , Custos Hospitalares/estatística & dados numéricos , Salas Cirúrgicas/organização & administração , Duração da Cirurgia , Cirurgiões/organização & administração , Adulto , Idoso , Feminino , Hospitais de Ensino/organização & administração , Humanos , Liderança , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Texas
10.
J Surg Res ; 200(1): 183-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26237993

RESUMO

BACKGROUND: During the course of evaluation for primary hyperaldosteronism, cross-sectional imaging is obtained in efforts to identify patients with an aldosterone producing adenoma (APA). A subset of these patients will have a synchronous, contralateral adrenal abnormality. Adrenal vein sampling (AVS) further guides clinical decision making by identifying unilateral (APA) versus bilateral hypersecretion. In the subset of patients with contralateral adrenal abnormalities, it is unclear how this affects the durability of an adrenalectomy for APA. This study characterizes this group of patients to assess the efficacy of surgical intervention. METHODS: A retrospective review of patients undergoing adrenalectomy for APA based on AVS at a university practice. Preoperative and postoperative patient characteristics, laboratory evaluations, imaging results, and final pathology were noted. RESULTS: From 2000 to 2011, 103 patients with APA underwent unilateral adrenalectomy. Eighteen patients (17%) had discordant results between AVS and imaging. Most of these patients were male (78%), and the mean age was 57 ± 13 y. Median duration of follow-up was 3.5 y [1 y, 6 y]. All patients with initial hypokalemia were rendered normokalemic after the operation. Four patients increased their antihypertensive regimen during the follow-up period. These patients all had nodular hyperplasia on final pathology. CONCLUSIONS: In patients with bilateral adrenal abnormalities who have undergone unilateral adrenalectomy for primary hyperaldosteronism, patients with clear APAs on final pathology appear to have durable outcomes after resection. Conversely, nodular hyperplasia on final pathology may be a risk factor for ongoing aldosterone hypersecretion. An algorithm for biochemical surveillance in this subset of patients should be considered.


Assuntos
Adenoma/diagnóstico , Neoplasias das Glândulas Suprarrenais/diagnóstico , Adrenalectomia , Hiperaldosteronismo/etiologia , Neoplasias Primárias Múltiplas/diagnóstico , Adenoma/complicações , Adenoma/cirurgia , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/cirurgia , Adulto , Idoso , Feminino , Seguimentos , Humanos , Hiperaldosteronismo/cirurgia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/complicações , Neoplasias Primárias Múltiplas/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
11.
Oncotarget ; 6(14): 12080-93, 2015 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-25900242

RESUMO

Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer of thyroid C-cells, for which few treatment options are available. We have recently reported a role for cyclin-dependent kinase 5 (CDK5) in MTC pathogenesis. We have generated a mouse model, in which MTC proliferation is induced upon conditional overexpression of the CDK5 activator, p25, in C-cells, and arrested by interrupting p25 overexpression. Here, we identify genes and proteins that are differentially expressed in proliferating versus arrested benign mouse MTC. We find that downstream target genes of the tumor suppressor, retinoblastoma protein, including genes encoding cell cycle regulators such as CDKs, cyclins and CDK inhibitors, are significantly upregulated in malignant mouse tumors in a CDK5-dependent manner. Reducing CDK5 activity in human MTC cells down-regulated these cell cycle regulators suggesting that CDK5 activity is critical for cell cycle progression and MTC proliferation. Finally, the same set of cell cycle proteins was consistently overexpressed in human sporadic MTC but not in hereditary MTC. Together these findings suggest that aberrant CDK5 activity precedes cell cycle initiation and thus may function as a tumor-promoting factor facilitating cell cycle protein expression in MTC. Targeting aberrant CDK5 or its downstream effectors may be a strategy to halt MTC tumorigenesis.


Assuntos
Carcinoma Medular/congênito , Ciclo Celular/genética , Quinase 5 Dependente de Ciclina/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2a/metabolismo , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Animais , Carcinogênese/genética , Carcinoma Medular/genética , Carcinoma Medular/metabolismo , Linhagem Celular Tumoral , Expressão Gênica , Humanos , Camundongos
13.
Cancer Cell ; 24(4): 499-511, 2013 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-24135281

RESUMO

Medullary thyroid carcinoma (MTC) is a neuroendocrine cancer that originates from calcitonin-secreting parafollicular cells, or C cells. We found that Cdk5 and its cofactors p35 and p25 are highly expressed in human MTC and that Cdk5 activity promotes MTC proliferation. A conditional MTC mouse model was generated and corroborated the role of aberrant Cdk5 activation in MTC. C cell-specific overexpression of p25 caused rapid C cell hyperplasia leading to lethal MTC, which was arrested by repressing p25 overexpression. A comparative phosphoproteomic screen between proliferating and arrested MTC identified the retinoblastoma protein (Rb) as a crucial Cdk5 downstream target. Prevention of Rb phosphorylation at Ser807/Ser811 attenuated MTC proliferation. These findings implicate Cdk5 signaling via Rb as critical to MTC tumorigenesis and progression.


Assuntos
Carcinoma Medular/metabolismo , Carcinoma Neuroendócrino/metabolismo , Quinase 5 Dependente de Ciclina/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias da Glândula Tireoide/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Progressão da Doença , Humanos , Camundongos , Camundongos Transgênicos , Fosforilação , Proteína do Retinoblastoma/metabolismo , Transdução de Sinais , Fatores de Tempo , Transgenes
14.
PLoS One ; 8(6): e65624, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23785438

RESUMO

BACKGROUND: Pheochromocytomas are rare tumors generally arising in the medullary region of the adrenal gland. These tumors release excessive epinephrine and norepinephrine resulting in hypertension and cardiovascular crises for which surgery is the only definitive treatment. Molecular mechanisms that control tumor development and hormone production are poorly understood, and progress has been hampered by the lack of human cellular model systems. To study pheochromocytomas, we developed a stable progenitor pheochromocytoma cell line derived from a primary human tumor. METHODS: After IRB approval and written informed consent, human pheochromocytoma tissue was excised, minced, dispersed enzymatically, and cultured in vitro. Primary pheochromocytoma cells were infected with a lentivirus vector carrying the catalytic subunit of human telomerase reverse transcriptase (hTERT). The hTERT immortalized cells (hPheo1) have been passaged >300 population doublings. The resulting cell line was characterized morphologically, biochemically and for expression of neuroendocrine properties. The expression of marker enzymes and proteins was assessed by immunofluorescence staining and immunoblotting. Telomerase activity was determined by using the telomeric repeat amplification protocol (TRAP) assay. RESULTS: We have established a human pheochromocytoma precursor cell line that expresses the neuroendocrine marker, chromogranin A, when differentiated in the presence of bone morphogenic protein 4 (BMP4), nerve growth factor (NGF), and dexamethasone. Phenylethanolamine N-methyltransferase (PNMT) expression is also detected with this differentiation regimen. CD-56 (also known as NCAM, neural cell adhesion molecule) is expressed in these cells, but CD31 (also known as PECAM-1, a marker of endothelial cells) is negative. CONCLUSIONS: We have maintained hTERT-immortalized progenitor cells derived from a pheochromocytoma (hPheo1) in culture for over 300 population doublings. This progenitor human cell line is normal diploid except for a deletion in the p16 region and has inducible neuroendocrine biomarkers. These cells should be a valuable reagent for studying mechanisms of tumor development and for testing novel therapeutic approaches.


Assuntos
Células-Tronco Neoplásicas/patologia , Feocromocitoma/patologia , Cariótipo Anormal , Adulto , Linhagem Celular Transformada , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Humanos , Imunofenotipagem , Células-Tronco Neoplásicas/metabolismo , Feocromocitoma/genética , Feocromocitoma/metabolismo , Interferência de RNA , Telomerase/genética , Telomerase/metabolismo , Transcriptoma , Transdução Genética
15.
Am J Physiol Heart Circ Physiol ; 302(9): H1847-59, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22408027

RESUMO

Using a mitochondria-targeted vitamin E (Mito-Vit-E) in a rat pneumonia-related sepsis model, we examined the role of mitochondrial reactive oxygen species in sepsis-mediated myocardial inflammation and subsequent cardiac contractile dysfunction. Sepsis was produced in adult male Sprague-Dawley rats via intratracheal injection of S. pneumonia (4 × 10(6) colony formation units per rat). A single dose of Mito-Vit-E, vitamin E, or control vehicle, at 21.5 µmol/kg, was administered 30 min postinoculation. Blood was collected, and heart tissue was harvested at various time points. Mito-Vit-E in vivo distribution was confirmed by mass spectrometry. In cardiac mitochondria, Mito-Vit-E improved total antioxidant capacity and suppressed H(2)O(2) generation, whereas vitamin E offered little effect. In cytosol, both antioxidants decreased H(2)O(2) levels, but only vitamin E strengthened antioxidant capacity. Mito-Vit-E protected mitochondrial structure and function in the heart during sepsis, demonstrated by reduction in lipid and protein oxidation, preservation of mitochondrial membrane integrity, and recovery of respiratory function. While both Mito-Vit-E and vitamin E suppressed sepsis-induced peripheral and myocardial production of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1ß, and interleukin-6), Mito-Vit-E exhibited significantly higher efficacy (P < 0.05). Stronger anti-inflammatory action of Mito-Vit-E was further shown by its near-complete inhibition of sepsis-induced myeloperoxidase accumulation in myocardium, suggesting its effect on neutrophil infiltration. Echocardiography analysis indicated that Mito-Vit-E ameliorated cardiac contractility of sepsis animals, shown by improved fractional shortening and ejection fraction. Together, our data suggest that targeted scavenging of mitochondrial reactive oxygen species protects mitochondrial function, attenuates tissue-level inflammation, and improves whole organ activities in the heart during sepsis.


Assuntos
Coração/efeitos dos fármacos , Inflamação/etiologia , Inflamação/prevenção & controle , Mitocôndrias Cardíacas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pneumonia Bacteriana/complicações , Sepse/complicações , Vitamina E/farmacologia , Animais , Antioxidantes/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Coração/fisiologia , Peróxido de Hidrogênio/metabolismo , Inflamação/metabolismo , Masculino , Mitocôndrias Cardíacas/fisiologia , Contração Miocárdica/efeitos dos fármacos , Contração Miocárdica/fisiologia , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Streptococcus pneumoniae
16.
Am J Physiol Cell Physiol ; 301(3): C695-704, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21653897

RESUMO

Endothelial migration is a crucial aspect of a variety of physiologic and pathologic conditions including atherosclerosis and vascular repair. Reactive oxygen species (ROS) function as second messengers during endothelial migration. Multiple intracellular sources of ROS are regulated by cellular context, external stimulus, and the microenvironment. However, the predominant source of ROS during endothelial cell (EC) migration and the mechanisms by which ROS regulate cell migration are incompletely understood. In this study, we tested the hypothesis that mitochondria-derived ROS (mtROS) regulate EC migration. In cultured human umbilical vein endothelial cells, VEGF increased mitochondrial metabolism, promoted mtROS production, and induced cell migration. Either the targeted mitochondrial delivery of the antioxidant, vitamin E (Mito-Vit-E), or the depletion of mitochondrial DNA abrogated VEGF-mediated mtROS production. Overexpression of mitochondrial catalase also inhibited VEGF-induced mitochondrial metabolism, Rac activation, and cell migration. Furthermore, these interventions suppressed VEGF-stimulated EC migration and blocked Rac1 activation in endothelial cells. Constitutively active Rac1 reversed Mito-Vit-E-induced inhibition of EC migration. Mito-Vit-E also attenuated carotid artery reendothelialization in vivo. These results provide strong evidence that mtROS regulate EC migration through Rac-1.


Assuntos
Movimento Celular/fisiologia , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator A de Crescimento do Endotélio Vascular/farmacologia , Animais , Lesões das Artérias Carótidas/patologia , Catalase/genética , Catalase/metabolismo , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , DNA Polimerase gama , DNA Polimerase Dirigida por DNA/genética , DNA Polimerase Dirigida por DNA/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/lesões , Endotélio Vascular/patologia , Endotélio Vascular/fisiologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , Regeneração/efeitos dos fármacos , Regeneração/fisiologia , Superóxidos/metabolismo , Transdução Genética , Vitamina E/farmacologia , Quinases Ativadas por p21/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismo , Fator de von Willebrand/metabolismo
17.
Cancer Cell ; 19(3): 297-9, 2011 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-21397852

RESUMO

Reactive oxygen species (ROS) mediate various cell fate decisions in normal and transformed cells. In this issue of Cancer Cell, Zhu et al. demonstrate the ability of ANGPTL4 to engage integrin-dependent survival signals by activation of the NADPH oxidase Nox1, thus mimicking anchorage conditions and bypassing anoikis by controlling ROS.


Assuntos
Angiopoietinas/metabolismo , Anoikis , Peróxido de Hidrogênio/metabolismo , Superóxidos/metabolismo , Proteína 4 Semelhante a Angiopoietina , Angiopoietinas/genética , Animais , Linhagem Celular Tumoral , Humanos , Integrinas/metabolismo , Camundongos , Camundongos Knockout , NADPH Oxidase 1 , NADPH Oxidases/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Ligação Proteica , Transdução de Sinais
18.
Surgery ; 148(6): 1267-72; discussion 1272-3, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21134560

RESUMO

BACKGROUND: Cytologically indeterminate thyroid nodules represent a diagnostic and therapeutic challenge. In 2007, the National Cancer Institute recommended The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) as a means of improving the accuracy of thyroid cytopathology. Our objective was to determine the effect of TBSRTC on thyroidectomy rates and malignancy risk in cytologically indeterminate lesions. METHODS: We compared thyroidectomy rates and malignancy risk in patients with indeterminate thyroid cytopathology across 2 time periods, spanning January 2000 and November 2009; pre-TBSRTC (January 2000 to September 2003) and post-TBSRTC (June 2008 to November 2009). Statistical comparisons were performed using the Fisher's exact test and chi-square analysis (P = .05 significant). RESULTS: We performed 938 fine-needle aspirations in the first period, 765 in the second. We identified 78 (8.3%) cytologically indeterminate lesions in the pre-TBSRTC group and 91 (11.9%) lesions in the post-TBSRTC group. We found no difference in thyroidectomy rates between the groups (37/78 [47%] pre-Bethesda versus 32/91 [35%] post-Bethesda; P = .12). However, the malignancy rate was significantly lower in the post-TBSRTC group (13/37 [35%] pre-Bethesda versus 4/32 [13%] post-Bethesda; P = .02). CONCLUSION: Application of TBSRTC is associated with lower malignancy risk in indeterminate thyroid nodules, despite similar thyroidectomy rates. These findings imply that standardization of cytologic classification improves diagnostic accuracy.


Assuntos
Biópsia por Agulha Fina/normas , Glândula Tireoide/patologia , Nódulo da Glândula Tireoide/cirurgia , Tireoidectomia/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha Fina/métodos , Distribuição de Qui-Quadrado , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , National Cancer Institute (U.S.) , National Institutes of Health (U.S.) , Estudos Retrospectivos , Medição de Risco , Nódulo da Glândula Tireoide/patologia , Tireoidectomia/estatística & dados numéricos , Estados Unidos
19.
Am J Physiol Heart Circ Physiol ; 298(6): H1951-8, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20348223

RESUMO

Studies from animal models suggest that myocardial mitochondrial damage contributes to cardiac dysfunction after burn injury. In this report, we used an ex vivo model of primary cardiomyocyte culture to investigate the mechanisms of burn-induced mitochondrial impairment. Briefly, blood serum was collected from Sprague-Dawley (SD) rats subjected to 40% total body surface area burn and added (10% vol/vol) to primary cardiomyocytes prepared from SD rats. The effect of the burn serum on mitochondrial function and membrane integrity in the myocytes was analyzed. Exposure of myocytes to burn serum doubled the mitochondrial membrane damage measured by two independent assays. This treatment also significantly elevated mitochondrial oxidative stress, indicated by a more than 30% increase in lipid oxidation. Downregulation of mitochondrial antioxidant defense was also evident since the activities of the antioxidant enzymes superoxide dismutase and glutathione peroxidase were reduced by about 30% and 50%, respectively. Burn serum also induced deficiency of mitochondrial metabolism, indicated by a 30% decrease in the activity of cytochrome c oxidase. These mitochondrial dysfunctions appear to be generated by oxidative stress because burn serum induced a significant increase of mitochondrial oxygen species (mtROS) in cardiomyocytes, and pretreatment of cardiomyocytes with the antioxidant N-acetyl-cysteine prevented the mitochondrial damages induced by burn serum. Remarkably, the increase in mtROS was abolished by an antibody-mediated blockade of CD14. Furthermore, burn injury-induced mitochondrial damage in cardiomyocytes was prevented in CD14 knockout mice. Taken together, these data suggested that burn injury produces CD14-dependent mitochondrial damage via oxidative stress in myocardium.


Assuntos
Queimaduras/sangue , Receptores de Lipopolissacarídeos/fisiologia , Mitocôndrias Cardíacas/fisiologia , Miócitos Cardíacos/fisiologia , Soro/fisiologia , Animais , Células Cultivadas , Glutationa Peroxidase/metabolismo , Receptores de Lipopolissacarídeos/genética , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/enzimologia , Membranas Mitocondriais/fisiologia , Modelos Animais , Miócitos Cardíacos/citologia , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/fisiologia , Superóxido Dismutase/metabolismo
20.
Ann Surg ; 249(2): 318-21, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19212188

RESUMO

OBJECTIVE: We hypothesized that an adrenal vein sampling (AVS) algorithm incorporating rapid cortisol assays, which enables resampling of the adrenal veins, would improve the success rate by a team of radiologists. SUMMARY BACKGROUND DATA: AVS is the most accurate means to localize aldosterone production in primary aldosteronism (PA). However, cannulation of the right adrenal vein (RAV) is difficult, and success is assumed from venography without the support of steroid assays. Furthermore, few institutions can assign all studies to 1 dedicated and experienced AVS interventional radiologist. METHODS: Retrospective chart review of patients with PA at our university hospitals who underwent AVS. We compared results for 30 AVS studies incorporating rapid cortisol assays with 30 conventional AVS studies. RESULTS: The success rate for the control period was 73% (22/30 studies). For the first 30 studies after incorporating rapid cortisol assay, the success rate increased to 97% (29/30 studies). Resampling the RAV was required for 2 studies, and prolonged sheath insertion did not cause any complications. CONCLUSIONS: High AVS success rates may be achieved by a team of interventional radiologists at 1 center using defined AVS protocols. Rapid cortisol assay allows for resampling of the RAV and improves AVS success rates.


Assuntos
Glândulas Suprarrenais/irrigação sanguínea , Hidrocortisona/sangue , Hiperaldosteronismo/sangue , Hiperaldosteronismo/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Feminino , Humanos , Hiperaldosteronismo/cirurgia , Imunoensaio , Masculino , Pessoa de Meia-Idade , Flebografia , Estudos Retrospectivos , Fatores de Tempo , Veias
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